Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: in vivo analysis of tumor-stromal interaction

• Published in: The Journal of immunology (1950) 2002-07, Vol.169 (1), p.469-475
• Main Authors: Saijo, Yasuo, Tanaka, Masashi, Miki, Makoto, Usui, Kazuhiro, Suzuki, Takuji, Maemondo, Makoto, Hong, Xin, Tazawa, Ryushi, Kikuchi, Toshiaki, Matsushima, Kouji, Nukiwa, Toshihiro
• Format: Article
• Language: English
• Subjects: Angiogenesis Inducing Agents - biosynthesis; Angiogenesis Inhibitors - pharmacology; Animals; Antibodies - pharmacology; Carcinoma, Lewis Lung - blood supply; Carcinoma, Lewis Lung - immunology; Carcinoma, Lewis Lung - metabolism; Carcinoma, Lewis Lung - pathology; Cell Communication - genetics; Cell Communication - immunology; Cell Division - immunology; Chemokine CXCL2; Chemokines - biosynthesis; Chemokines - metabolism; Cyclohexanes; Endothelial Growth Factors - biosynthesis; Endothelial Growth Factors - metabolism; Gene Transfer Techniques; Hepatocyte Growth Factor - biosynthesis; Hepatocyte Growth Factor - genetics; Humans; Immunohistochemistry; Inflammation - immunology; Interleukin-1 - biosynthesis; Interleukin-1 - genetics; Interleukin-1 - physiology; Lymphokines - biosynthesis; Lymphokines - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; O-(Chloroacetylcarbamoyl)fumagillol; Receptors, Interleukin-8B - immunology; Sesquiterpenes - pharmacology; Species Specificity; Stromal Cells - immunology; Stromal Cells - metabolism; Stromal Cells - pathology; Tumor Cells, Cultured; Up-Regulation - genetics; Up-Regulation - immunology; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.169.1.469

Inflammatory conditions are associated with tumor development. IL-1beta is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1beta in tumor growth in vivo, we transduced the retroviral vector coding human IL-1beta gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1beta) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1beta grew faster (240%, day 18, vs null-vector control LLC/neo; p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1beta cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1beta cells secreted 2-fold the amount of vascular endothelial growth factor and >10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1beta itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1beta cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1beta tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1beta cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1beta cells in vivo. These results indicated that secreting IL-1beta into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.